Immunophilin ligand treatment of antiretroviral toxic neuropathy

a technology of toxic neuropathy and immunoglobulin, which is applied in the field of immunoglobulin ligand treatment of toxic neuropathy, can solve the problems of not only affecting the quality of life of patients, severely restricting viral suppression strategies, and discontinuing offending drugs in a particular patient. it prevents the development of neurotoxicity, severely restricts viral suppression strategies, and affects the quality of li

Inactive Publication Date: 2005-06-16
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0016] d) identifying an immunophilin ligand which results in preventing reduction in the number of neurites and total neuritic length per neuron due to the treatment with NRTI.
[0023] Antiretroviral toxic neuropathy (ATN) is the most common neurological complication of HIV infection. This painful neuropathy not only affects the quality of life of HIV-infected patients but also severely limits viral suppression strategies. The present invention relates to in vitro models of this toxic neuropathy that mimics the in vivo situation in that ddC appears to be the most neurotoxic, followed by ddl and then d4T. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in the models of the present invention. In these models, the immunophilin ligand FK506 prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced ‘neuritic pruning’, neuronal mitochondrial depolarization and neuronal necrotic death. The in vitro models of the present invention are highly useful screening tools to test the efficacy of promising neuroprotective or regenerative agents in the prevention or treatment of ATN.

Problems solved by technology

Because the presently available symptomatic therapies are poorly efficacious the development of ATN often results in discontinuation of the offending drug in a particular patient.
As these drugs are an essential component of highly active antiretroviral therapy (HAART) and substantially reduce the morbidity and mortality of HIV infection, this associated toxic sensory neuropathy not only affects quality of life, but also severely limits viral suppression strategies.
Development of therapeutic drugs for treatment or prevention of ATN is hampered by the fact that there are no good established in vivo or in vitro models of NRTI-induced sensory neuropathy.
A drawback to the clinical use of FK506 as a neuroprotective agent is that it is also a potent immunosuppressant due to inhibition of calcineurin-dependent dephosphorylation of NFAT.

Method used

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  • Immunophilin ligand treatment of antiretroviral toxic neuropathy

Examples

Experimental program
Comparison scheme
Effect test

example 1

NRTIs Cause Dose-Dependent Neurotoxicity on Primary DRG Sensory Neuronal Cultures

[0089] In order to assess the effects of NRTIs on established neurites primary DRG neurons were plated on a Schwann cell monolayer and allowed to extend their neurites for about 3 hours in the presence of GDNF-containing medium. At this early stage, most neurons had neurites that were at least 100 microns in length. Then added varying doses of NRTIs or vehicle control were added, before fixing and immunostaining the cultures 15 hours later. FIG. 1 (A-D) shows representative confocal microscope fields from a vehicle control culture and cultures treated with varying doses of ddC. In the control cultures, most neurons bore several neurites that were at least 200-300 microns in length and had many branching points. Morphological dose-dependent changes were noted in the ddC-treated neurons. At low ddC concentrations, varicosities were seen in the most distal portions of the neurites, away from the cell body...

example 2

FK506 Prevents the Development of ddC-Induced Neurotoxicity in Primary DRG Neurons

[0090] To test whether FK506 may prevent NRTI neurotoxicity in primary DRG sensory neurons, ss before, neurons were plated for 3 hours for the establishment of neurites. Then added ddC (10 μM) was added with or without FK506 and morphological changes were analyzed 15 hours later. As seen in FIG. 2 very low doses of FK506 prevented the reduction in number of neurites per neuron and total neuritic length by ddC. In contrast to FK506, CSA was not effective in preventing this neurotoxicity. In the absence of ddC, FK506 did not have any appreciable effect on the morphological parameters used in the study.

example 3

NRTI Neurotoxicity is Associated with Loss of Δ-σ in Neuronal Mitochondria Four Hours after Exposure

[0091] JC-1 is a lipophilic, cationic dye that emits green fluorescence at low concentrations when it is in monomeric form but emits a red fluorescence when aggregated. In healthy mitochondria with an intact membrane potential differential (Δ-σ), the fluorescence emission pattern of JC-1 exhibits a high red: green luminosity ratio, while in depolarized mitochondria, this ratio is low. Tetanus Toxin C-fragment was used as a live neuronal marker in our mixed DRG neuronal / Schwann cell cultures, and FCCP, a protonophore and uncoupler of oxidative phosphorylation, served as a positive control since it is a prototypic depolarizer of mitochondrial membrane. In vehicle control cultures, TTC-labeled neurons emitted mainly red and little green fluorescence (FIG. 3). The reverse was true for both the ddC- and FCCP-treated cultures, suggesting loss of mitochondrial membrane potential. FIG. 4 gra...

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Abstract

The present invention relates to in vitro models of identifying non-immunosuppressive immunophilin ligands that are useful in the treatment or prevention of peripheral neuropathies. Other embodiments of the present invention include methods of using non-immunosuppressive immunophilin ligands for the treatment of antiretroviral toxic neuropathies.

Description

PRIORITY [0001] The present application claims priority to U.S. Provisional Application No. 60 / 466,650, filed Apr. 30, 2003.FIELD OF THE INVENTION [0002] The field of the invention relates to in vitro models for identifying agents that are useful in the treatment or prevention of human neuropathies. BACKGROUND OF THE INVENTION [0003] HIV-associated sensory neuropathies are the most common neurological complications in HIV infection, clinically affecting about 30% of patients with AIDS. These include distal sensory polyneuropathy (DSP), associated with HIV infection per se, and antiretroviral toxic neuropathy (ATN), associated with Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs), particularly ddC, ddl and d4T (reviewed in (Wulff et al., 2000)). Because the presently available symptomatic therapies are poorly efficacious the development of ATN often results in discontinuation of the offending drug in a particular patient. As these drugs are an essential component of highl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439G01N33/50
CPCA61K31/4439G01N2800/52G01N33/5052
Inventor HOKE, AHMETGRIFFIN, JOHN W.KESWANI, SANJAY C.MCARTHUR, JUSTIN C.
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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